The overall objective of this proposal is to further elucidate and characterize the interaction of epidermal growth factor (EGF) with its target cells. EGF has been shown to be a potent mitogen for a number of cell types, including liver. Specifically, we intend to examine the binding of EGF to rat hepatocyte nuclei in an effort to confirm and extend our preliminary data which indicates that nuclear receptors for the growth factor exist. Nuclei from both intact adult rat liver and from adult rat liver parenchymal cells in primary culture will be used in order to examine both the in vivo and in vitro situation. Radioiodinated EGF will be used for the binding studies. Analysis of the data will include calculation of the number of EGF receptors per nucleus and the affinity of these receptors for EGF. Comparisons will then be made to published data for the plasma membrane EGF receptor. The sub-nuclear location of the EGF receptors will also be determined by fractionating the nuclei and measuring EGF binding to each of the fractions. These studies will aid in the assessment of the role of EGF internalization by its target cells. Additionally, if nuclear receptors for EGF are demonstrated conclusively, then direct effects of EGF on nuclear functions may be further examined to determine the precise mechanism by which EGF, and possibly other polypeptide hormones and growth factors, alter the growth characteristics and differentiated function of various cell types. Answers to these questions will have far-reaching impact on our understanding of the nature of normal and abnormal cellular proliferation and differentiation.